TCA-cycle metabolites in the nucleus: drivers of chromatin and epigenetic control

Mitochondrial enzymes are increasingly recognized for their ability to translocate to the nucleus, where they generate metabolites essential for epigenetic regulation and gene expression. Yet, whether this phenomenon broadly involves metabolic enzymes or is restricted to specific subunits remains unclear. In this review, we assess current evidence, highlight knowledge gaps, and suggest future directions on the nuclear localization and functions of metabolic enzymes, with a focus on acyl-CoA producers. Emerging studies reveal multiple mechanisms guiding these enzymes to chromatin for localized metabolite synthesis. Key questions concern nuclear import machinery, chromatin interactions, and the regulatory impact of their activity.